16-2109556-C-T

Variant names:

• chr16-2109556-C-T
• rs144137200
• NM_001009944.3:c.5611G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.5611G>A​(p.Ala1871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,611,596 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1871G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (54 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.33
• Publications: 13 publications found

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0155184865).
• BP6: Variant 16-2109556-C-T is Benign according to our data. Variant chr16-2109556-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00434 (661/152352) while in subpopulation NFE AF = 0.00731 (497/68024). AF 95% confidence interval is 0.00678. There are 1 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 54 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.5611G>A	p.Ala1871Thr	missense	Exon 15 of 46	ENSP00000399501.1
	PKD1	ENST00000487932.5	TSL:5	n.298G>A		non_coding_transcript_exon	Exon 1 of 30	ENSP00000457132.1

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00731

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00425 AC: 1044 AN: 245780 AF XY: 0.00449

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00466

GnomAD4 exome AF: 0.00671 AC: 9789 AN: 1459244 Hom.: 54 Cov.: 34 AF XY: 0.00663 AC XY: 4810 AN XY: 725874

African (AFR) AF: 0.000926 AC: 31 AN: 33460

American (AMR) AF: 0.00249 AC: 111 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.00598 AC: 515 AN: 86100

European-Finnish (FIN) AF: 0.00161 AC: 84 AN: 52014

Middle Eastern (MID) AF: 0.00255 AC: 14 AN: 5490

European-Non Finnish (NFE) AF: 0.00782 AC: 8692 AN: 1111496

Other (OTH) AF: 0.00561 AC: 338 AN: 60280

GnomAD4 genome AF: 0.00434 AC: 661 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00391 AC XY: 291 AN XY: 74508

African (AFR) AF: 0.00149 AC: 62 AN: 41586

American (AMR) AF: 0.00353 AC: 54 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00731 AC: 497 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00370 Hom.: 2

Bravo AF: 0.00479

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00572 AC: 49

ExAC AF: 0.00411 AC: 495

EpiCase AF: 0.00780

EpiControl AF: 0.00719

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Feb 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17582161, 22608885, 30647506)

Feb 25, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.5611G>A (p.Ala1871Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0042 in 245780 control chromosomes, predominantly at a frequency of 0.0066 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. To our knowledge, no occurrence of c.5611G>A in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 256979). Based on the evidence outlined above, the variant was classified as likely benign.

Polycystic kidney disease, adult type Benign:2

Sep 25, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polycystic kidney disease Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Ala1871Thr variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD, being classified as a polymorphism/likely neutral (Rossetti 2007, Rossetti 2012, Tan 2009, Tan 2014). The variant was identified in dbSNP (ID: rs144137200) as “With Likely benign allele”, Clinvitae and ClinVar (classification likely benign, submitter Prevention Genetics), and the ADPKD Mutation Database (classification likely neutral); but was not identified in GeneInsight-COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), HAPMAP-EUR in 3 of 1006 chromosomes (frequency: 0.003)/-AMR in 3 of 694 chromosomes (frequency: 0.0043)/-SAS in 2 of 978 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 49 of 8560 European American alleles (freq. 0.006) and in 6 of 4374 African American alleles (freq. 0.001), the genome Aggregation Database (beta, October 19th 2016) in 1142 (4 homozygous) of 272522 chromosomes (freq. 0.004) and in the Exome Aggregation Consortium database (August 8th 2016) 485 (4 homozygous) of 104730 chromosomes (freq. 0.0046) in the following populations: European (Non-Finnish) in 364 of 57774 chromosomes (freq. 006), South Asian in 84 of 15042 chromosomes (freq. 006), Other in 4 of 732 chromosomes (freq. 006), Latino in 20 of 10302 chromosomes (freq. 002), African in 10 of 8320 chromosomes (freq. 001), and in European (Finnish) in 3 of 4634 chromosomes (freq. 0006); but was not seen in East Asian; increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala1871 residue is not conserved in mammals and 4 out of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

PKD1-related disorder Benign:1

Jun 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.027
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.22
MVP		0.92
ClinPred		0.015	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.39
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144137200; hg19: chr16-2159557; COSMIC: COSV99239466; COSMIC: COSV99239466;